The lesions of atherosclerosis have been hypothesized to represent a response of the artery wall to various forms of injury and have many of the features of the inflammatory response in other tissues. One common feature of lesions of atherosclerosis, at all stages of lesion development, is the ubiquitous presence of monocyte/macrophages. Activated macrophages are a potential source of numerous mediators that may be involved in lesion development and progression. Our studies will focus on the expression of monocyte/macrophage-derived mediators of chemotaxis and proliferation of monocytes, endothelial cells and smooth muscle cells. The directed migration and proliferation of monocytes and smooth muscle cells are critical processes in the evolution of the lesions to clinically relevant states. The expression of endothelial cell chemoattractants and growth modulators may also affect lesion progression and neovascularization associated with advanced lesions and may be necessary for repair of endothelial injury. Which monocyte/macrophage-derived mediators of chemotaxis and proliferation are expressed during the different stages of lesion development? How is their expression regulated by foam cell formation or by different forms of macrophage activation? How do antioxidants alter the expression of these mediators? The interactions between monocytes and endothelium that precede the entry of the monocytes into the artery wall represent critical events in the process of atherogenesis. Insights into these interactions may be developed by studying endothelium and smooth muscle derived from sites that are more resistant to atherosclerosis like the brachial and mesenteric arteries as compared to those that are susceptible like the lilac arteries and abdominal aorta. This proposal will examine the roles of the monocyte/macrophage in its continuing interactions with endothelium and smooth muscle in atherogenesis.